Exhaled Nitric Oxide and Exhaled Breath Condensate

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Description:

Current techniques for diagnosing and monitoring asthma and predicting exacerbations are peak flow measurement and spirometry. Two new strategies, evaluation of exhaled nitric oxide (NO) and exhaled breath condensate are proposed. These techniques are also potentially useful in the management of other conditions such as chronic obstructive pulmonary disease (COPD) and chronic cough. There are commercially available devices for measuring NO in expired breath and various laboratory techniques for evaluating components of exhaled breath condensate.

Guidelines for the management of persistent asthma stress the importance of long-term suppression of inflammation using steroids, leukotriene inhibitors, or other anti-inflammatory drugs. Existing techniques for monitoring the status of underlying inflammation have focused on bronchoscopy, with lavage and biopsy, or analysis by induced sputum. Current standards in the assessment of asthma focuses not on the status of the underlying chronic inflammation, but rather on regular assessments of respiratory parameters such as forced expiratory volume in one second (FEV1) and peak flow. There has been interest in noninvasive techniques to assess the underlying pathogenic chronic inflammation as reflected by measurements of inflammatory mediators. Two proposed strategies are the measurement of exhaled nitric oxide (NO) and the evaluation of exhaled breath condensate.

Exhaled nitric oxide (NO)

Nitric oxide is an important endogenous messenger and inflammatory mediator that is widespread in the human body, functioning, for example, to regulate peripheral blood flow, platelet function, immune reactions, and neurotransmission and to mediate inflammation. In biologic tissues, NO is unstable, limiting measurement. However, in the gas phase, NO is fairly stable, permitting its measurement in exhaled air. Exhaled NO is typically measured during single breath exhalations. First, the subject inspires nitric oxide-free air via a mouthpiece until total lung capacity is achieved, followed immediately by exhalation through the mouthpiece into the measuring device. Several devices measuring exhaled NO are commercially available in the United States. According to a 2009 joint statement by the American Thoracic Society (ATS) and European Respiratory Society (ERS), there is a consensus that the fractional concentration of exhaled nitric oxide (FeNO) is best measured at an exhaled rate of 50 mL per second (FeNO 50 mL/s) maintained within 10% for more than 6 seconds at an oral pressure between 5 and 20 cm H2O. (1) Results are expressed as the NO concentration in parts per billion (ppb), based on the mean of 2 or 3 values.

Exhaled breath condensate (EBC)

Exhaled breath condensate (EBC) consists of exhaled air passed through a condensing or cooling apparatus, resulting in an accumulation of fluid. Although EBC is primarily derived from water vapor, it also contains aerosol particles or respiratory fluid droplets, which in turn contain various nonvolatile inflammatory mediators, such as cytokines, leukotrienes, oxidants, antioxidants, and various other markers of oxidative stress. There are a variety of laboratory techniques to measure the components of EBC, including such simple techniques as pH measurement, to the more sophisticated gas chromatography/mass spectrometry or high performance liquid chromatography, depending on the component of interest.

Measurement of NO and EBC has been investigated in the diagnosis and management of asthma. Potential uses in management of asthma include assessing response to anti-inflammatory treatment, monitoring compliance with treatment, and predicting exacerbations. Aside from asthma, they have also been proposed in the management of patients with chronic obstructive pulmonary disease (COPD), cystic fibrosis, allergic rhinitis, and primary ciliary dyskinesia.

The following devices/systems have been cleared for marketing by the FDA:

The Apieron INSIGHT™ eNO System received 510(K) approval on March 14, 2008.

The RTube Exhaled Breath Condensate collection system (Respiratory Research, Inc) is registered with the FDA as a Class I device that collects expired gas. Respiratory Research has a proprietary gas-standardized pH assay, which, when performed by the company, is considered a laboratory-developed test.

American Thoracic Society (ATS)/European Respiratory Society (ERS)

The ATS/ERS statement includes the following recommendations regarding use of biomarkers in clinical practice:

Where possible, biomarkers should be employed to provide information about underlying airway inflammation, a domain of the asthma ‘‘syndrome’’ that would not otherwise be available to the clinician

FENO measurements may be used as a surrogate marker for eosinophilic airway inflammation. They may be used to evaluate the potential for response to corticosteroid treatment.

Low values of FENO (< 25 ppb in adults, < 20 ppb in children) may be of particular value in aiding decisions about reducing corticosteroid dose, or alternatively for determining that ongoing airway symptoms are well managed.

The authors acknowledge that more information is required on the utility of FENO measurement as a tool for monitoring asthma control, and that here is a need for translational research to clarify the relationship between biomarkers and other parameters of asthma control, to establish the optimal frequency of monitoring, and to confirm the clinical and cost effectiveness of biomarker measurements in primary care and other settings.

Regarding exhaled breath condensate, the statement concludes that more work is needed on the validation of the various measures from EBC, and to describe the relationship between these measures and other markers of asthma control. The authors concluded that studies to address whether using EBC results in improved clinical decision-making or better asthma outcomes are required.

Measurement of exhaled nitric oxide is considered investigational in the diagnosis and management of asthma and all other disorders including but not limited to chronic obstructive pulmonary disease and chronic cough.

Measurement of exhaled breath condensate is considered investigational in the diagnosis and management of asthma and all other disorders including but not limited to chronic obstructive pulmonary disease and chronic cough.

The evidence is insufficient to determine the effect of exhaled nitric oxide and exhaled breath condensate tests on health outcomes. The recent studies do prove that there is treatment change with the addition of FeNO measurements, but fail to examine the effect of the treatment changes on outcomes. There is still no validated standardized cutoff of FeNO to use for diagnosing asthma. As a result, it is not possible to determine the true sensitivity and specificity of the test for diagnosing asthma or any other disorder. Inhaled steroids are a mainstay of treatment of asthma and have been associated with a variety of health outcome benefits. The change in management must be examined to determine net benefits on health outcomes.

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